Associations of COVID-19 Symptoms with Omicron Subvariants BA.2 and BA.5, Host Status, and Clinical Outcomes: A Registry-Based Observational Study in Sapporo, Japan

Background Previous SARS-CoV-2 infection and vaccination, coupled to rapid evolution of SARS-CoV-2 variants, have modified COVID-19 clinical manifestations. We characterized clinical symptoms of COVID-19 individuals in omicron BA.2 and BA.5 Japanese pandemic periods to identify omicron and subvariant associations between symptoms, immune status, and clinical outcomes. Methods Individuals registered in Sapporo’s web-based COVID-19 information system entered 12 pre-selected symptoms, days since symptom onset, vaccination history, SARS-CoV-2 infection history, and background. Symptom frequencies, variables associated with symptoms, and symptoms associated with progression to severe disease were analysed. Results For all omicron-infected individuals, cough was the most common symptom (62.7%), followed by sore throat (60.7%), nasal discharge (44.3%), and fever (38.8%). Omicron BA.5 infection was associated with a higher symptom burden than BA.2 in vaccinated and unvaccinated individuals. Omicron breakthrough-infected individuals with ≥ 3 vaccinations or previous infection were less likely to exhibit systemic symptoms, but more likely to exhibit upper respiratory symptoms. Infected elderly individuals had lower odds for all symptoms, but, when symptoms were manifest, systemic symptoms were associated with an increased risk, whereas upper respiratory symptoms with a decreased risk, of severe disease. Conclusion Host immunological status, omicron subvariant, and age were associated with a spectrum of COVID-19 symptoms and outcomes. BA.5 produced a greater symptom burden than BA.2. Vaccination and prior infection mitigated systemic symptoms and improved outcomes, but increased upper respiratory tract symptom burden. Systemic, but not upper respiratory, symptoms in the elderly heralded severe disease. ### Competing Interest Statement IY reports grants from the Japan Agency for Medical Research and Development (AMED), as well as Health, Labour and Welfare Policy Research Grants, and speaker fees from Chugai Pharmaceutical Co., and AstraZeneca, outside the submitted work. The other authors declare that they have no conflict of interest. ### Funding Statement This project was supported in part by AMED under Grant JP223fa627005 and JP21zf0127004, the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK065988 to RCB), the Cystic Fibrosis Foundation (RDP BOUCHE15R0 to RCB; BOUCHE19XX0 to RCB and KO; OKUDA20G0 to KO), and a research grant from the Cystic Fibrosis Research Institute to KO. This project was also partially supported by the Rapidly Emerging Antiviral Drug Development Initiative at the University of North Carolina at Chapel Hill, funded by the North Carolina coronavirus state and local fiscal recovery funds program appropriated by the North Carolina General Assembly, and by the project of junior scientist promotion at Hokkaido University. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The research protocol was approved by the Ethics Committee of Hokkaido University Hospital (Research No. 022-0225). Analysis was performed using database in Sapporo city, with no additional risks to the patients. Therefore, the requirement for informed consent from individual participants was waived by the ethics committee. All methods were performed in accordance with the relevant guidelines and regulations of the Ethics Committee of Hokkaido University Hospital. All patient data were anonymized. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The original data is confidential to the City of Sapporo and cannot be made public. All data produced in the present work are contained in the manuscript.